title: Interactions between GSK3β and amyloid genes explain variance in amyloid burden.
abstract: The driving theoretical framework of Alzheimer's disease (AD) has been built around the amyloid-β (Aβ) cascade in which amyloid pathology precedes and drives tau pathology. Other evidence has suggested that tau and amyloid pathology may arise independently. Both lines of research suggest that there may be epistatic relationships between genes involved in amyloid and tau pathophysiology. In the current study, we hypothesized that genes coding glycogen synthase kinase 3 (GSK-3) and comparable tau kinases would modify genetic risk for amyloid plaque pathology. Quantitative amyloid positron emission tomography data from the Alzheimer's Disease Neuroimaging Initiative served as the quantitative outcome in regression analyses, covarying for age, gender, and diagnosis. Three interactions reached statistical significance, all involving the GSK3β single nucleotide polymorphism rs334543-2 with APBB2 (rs2585590, rs3098914) and 1 with APP (rs457581). These interactions explained 1.2%, 1.5%, and 1.5% of the variance in amyloid deposition respectively. Our results add to a growing literature on the role of GSK-3 activity in amyloid processing and suggest that combined variation in GSK3β and APP-related genes may result in increased amyloid burden.
authors.affiliation: Center for Human Genetics and Research, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: Timothyjhohman@gmail.com.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hohman
authors.forename: Mary Ellen I
authors.initials: ME
authors.lastname: Koran
authors.forename: Tricia A
authors.initials: TA
authors.lastname: Thornton-Wells
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase
keywords: ADNI; Alzheimer's disease; Amyloid; Imaging genetics; PET; Tau